EFONIDIPINE
DESCRIPTION
EFONIDIPINE IS A CALCIUM CHANNEL BLOCKER OF THE DIHYDROPYRIDINE CLASS, COMMERCIALIZED BY SHIONOGI & CO. (JAPAN). INITIALLY, IT WAS MARKETED IN 1995 UNDER THE TRADE NAME, LANDEL. THE DRUG HAS BEEN SHOWN TO BLOCK T-TYPE IN ADDITION TO L-TYPE CALCIUM CHANNELS ,. IT HAS ALSO BEEN STUDIED IN ATHEROSCLEROSIS AND ACUTE RENAL FAILURE . THIS DRUG IS ALSO KNOWN AS NZ-105, AND SEVERAL STUDIES HAVE BEEN DONE ON ITS PHARMACOKINETICS IN ANIMALS 13 .
INDICATION
FOR THE TREATMENT OF HYPERTENSION.
PHARMACODYNAMICS
DIHYDROPYRIDINES (DHPS), ACT MAINLY ON L-TYPE CALCIUM CHANNELS, ESSENTIALLY CAUSING REFLEX TACHYCARDIA, WHICH NEGATIVELY AFFECTS CARDIAC FUNCTION. THIS LEADS TO A DECREASE IN BLOOD PRESSURE AND AN INCREASE IN HEART RATE. EFONIDIPINE ACTS ON BOTH L-TYPE AND T-TYPE CALCIUM CHANNELS. BECAUSE INHIBITION OF T-TYPE CALCIUM CHANNELS IN THE SINOATRIAL (SA NODE) NODE ATTENUATE REFLEX TACHYCARDIA, THIS DRUG FAVORABLY AFFECTS CARDIAC PACING. THE EFFECT OF EFONIDIPINE ON HEART RATE DESERVES SPECIAL RECOGNITION WITH REGARD TO REFLEX TACHYCARDIA, DUE TO ITS UNIQUE EFFECTS IN RELATION TO OTHER DRUGS IN ITS CLASS .
MECHANISM OF ACTION
THIS DRUG INHIBITS THE L-TYPE AND T-TYPE CALCIUM CHANNELS, THEREBY LEADING TO VASODILATION AND DECREASED AUTOMATICITY OF THE HEART. EFONIDIPINE EXERTS NEGATIVE CHRONOTROPIC EFFECTS, DECREASING HEART RATE. ACTING ON SA NODE CELLS BY INHIBITING T-TYPE CALCIUM CHANNEL ACTIVITY, EFONIDIPINE PROLONGS THE LATE PHASE-4 DEPOLARIZATION OF THE SINOATRIAL NODE ACTION POTENTIAL, DECREASING HEART RATE. THIS IS ASSOCIATED WITH DECREASED MYOCARDIAL OXYGEN DEMAND AND INCREASES OF BLOOD FLOW TO THE CORONARY ARTERIES AND THEREBY ATTENUATES MYOCARDIAL ISCHEMIA. EFONIDIPINE INCREASES GLOMERULAR FILTRATION RATE (GFR) WITHOUT INCREASING INTRA-GLOMERULAR PRESSURE AND FILTRATION FRACTION ,, . THIS INCREASE LEADS TO THE PREVENTION OF RENAL DAMAGE THAT IS NORMALLY ASSOCIATED WITH HYPERTENSION.
EFONIDIPINE INCREASES THE RATE OF RENAL SODIUM EXCRETION VIA THE SUPPRESSION OF ALDOSTERONE SYNTHESIS AND ALDOSTERONE SECRETION FROM THE ADRENAL GLANDS. ALDOSTERONE-INDUCED RENAL PARENCHYMAL FIBROSIS IS SAID TO BE SUPPRESSED BY EFONIDIPINE .
L-TYPE CALCIUM CHANNEL BLOCKERS, SUCH AS EFONIDIPINE, PREFERENTIALLY DILATE AFFERENT ARTERIOLES IN THE KIDNEY, WHEREAS BOTH L-/T-TYPE AND L-/N-TYPE CALCIUM CHANNEL BLOCKERS POTENTLY DILATE BOTH AFFERENT AND EFFERENT ARTERIOLES. THE DISTINCT ACTIONS OF CALCIUM CHANNEL BLOCKERS ON THE RENAL MICROCIRCULATION ARE DEMONSTRATED BY CHANGES IN GLOMERULAR CAPILLARY PRESSURE AND SUBSEQUENT RENAL INJURY: L-TYPE CALCIUM CHANNEL BLOCKERS FAVOR AN INCREASE IN GLOMERULAR CAPILLARY PRESSURE, WHEREAS L-/T-TYPE AND L-/N-TYPE CCBS ALLEVIATE GLOMERULAR HYPERTENSION. THIS SUPPORTS THE THEORY THAT L-TYPE/T-TYPE CALCIUM CHANNEL BLOCKERS MAY BE OF BENEFIT IN RENAL HYPERTENSION . EFONIDIPINE IS A LONG-ACTING MEDICATION DUE TO A LOW DISSOCIATION CONSTANT 11 .
RECENT STUDIES SUGGEST THAT EFONIDIPINE REDUCES PLASMA ALDOSTERONE LEVELS IN PATIENTS ON REGULAR HEMODIALYSIS, WHICH IS OF ADDITIONAL BENEFIT TO THE CARDIOVASCULAR PROTECTION BY ANTIHYPERTENSIVE THERAPY WITH EFONIDIPINE IN PATIENTS WITH END-STAGE RENAL DISEASE .
TARGET ACTIONS ORGANISM
UVOLTAGE-DEPENDENT T-TYPE CALCIUM CHANNEL SUBUNIT ALPHA-1I ANTAGONISTHUMANS
UVOLTAGE-DEPENDENT L-TYPE CALCIUM CHANNEL SUBUNIT ALPHA-1C NOT AVAILABLEHUMANS
ABSORPTION
THE METABOLISM OF EFONIDIPINE WAS STUDIED IN RATS. THE ABSORPTION RATIO OF RADIOACTIVITY ESTIMATED FROM THE SUM OF BILIARY AND URINARY EXCRETIONS WAS FOUND TO BE APPROXIMATELY 62% 14 . THE RADIOACTIVITY WAS HIGH IN THE GASTROINTESTINAL TRACT AND LIVER, FOLLOWED BY THE ADRENAL GLANDS 14 , SUGGESTING HIGH RATES OF METABOLISM IN THESE REGIONS.
THE UNCHANGED DRUG IN THE PLASMA ACCOUNTED FOR 47.7% OF RADIOACTIVITY AT 2HR AFTER INGESTION, DEMONSTRATING A LOWER FIRST-PASS EFFECT IN COMPARISON WITH OTHER DRUGS IN THE SAME CLASS. IN PLASMA, MAJOR METABOLITES OF NZ-105 WERE: N-DEBENZYLATED COMPOUND (DBZ), N-DEPHENYLATED COMPOUND (DPH), OXIDATIVE DEAMINATED COMPOUND (AL), AL-CORRESPONDING PYRIDINE COMPOUND (ALP), UNKNOWN METABOLITE M-1 AND M-25. NZ-105 WAS METABOLIZED BY N-DEBENZYLATION, N-DEPHENYLATION, OXIDATIVE DEAMINATION, ESTER HYDROLYSIS AND OXIDATION OF 1, 4-DIHYDROPYRIDINE RING TO ITS CORRESPONDING PYRIDINE 14 .
VOLUME OF DISTRIBUTION
NOT AVAILABLE
PROTEIN BINDING
NOT AVAILABLE
METABOLISM
IT HAS BEEN SUGGESTED THAT EFONIDIPINE IS LESS LIKELY TO BE SUBJECT TO THE FIRST-PASS THAN OTHER MEMBERS OF ITS DRUG CLASS, AND AND THAT ITS DIHYDROPYRIDINE RING IS OXIDIZED PRIMARILY AFTER METABOLISM OF THE SIDE CHAIN . EFONIDIPINE IS HIGHLY LIPOPHILIC AND THIS ALLOWS FOR ITS ENTRY INTO THE PHOSPHOLIPID-RICH CELL MEMBRANE AND REACH THE DIHYDROPYRIDINE BINDING SITE OF THE CALCIUM CHANNEL TARGETS 10 .
EFONIDIPINE IS MAINLY METABOLIZED IN THE LIVER. ITS METABOLITES ARE N-DEPHENYLATED EFONIDIPINE (DPH), DEAMINATED EFONIDIPINE (AL) AND N-DEBENZYLATED EFONIDIPINE (DBZ). BOTH METABOLITES BEHAVE AS CALCIUM ANTAGONISTS. IN ONE STUDY, THE VASODILATING CAPABILITIES OF DBZ AND DPH WERE ABOUT TWO-THIRDS AND ONE-THIRD RESPECTIVELY THAN THAT OF THE UNMETABOLIZED DRUG. RESEARCH SUGGESTS THAT THE MAJORITY OF THE PHARMACOLOGICAL EFFECT AFTER ORAL DOSING OF EFONIDIPINE HYDROCHLORIDE IS DUE TO UNCHANGED DRUG AND ITS METABOLITES PLAY LITTLE ROLE IN ITS THERAPEUTIC EFFECT.
IN A STUDY OF SIX HEALTHY VOLUNTEERS, NO SIGNIFICANT AMOUNT OF UNCHANGED DRUG WAS EXCRETED IN URINE. THE URINE SAMPLES COLLECTED FOR 24?H AFTER ORAL EFONIDIPINE ADMINISTRATION, 1.1% OF THE DOSE WAS EXCRETED AS DEAMINATED-EFONIDIPINE, AND 0.5% AS A PYRIDINE ANALOGUE OF DEAMINATED-EFONIDIPINE 14 .
ROUTE OF ELIMINATION
EFONIDIPINE IS ALSO REFERRED TO AS NZ-105 13 AND HAS BEEN FOUND TO BE MAINLY ELIMINATED BY THE BILIARY SYSTEM 14 .
HALF LIFE
THE PEAK PLASMA CONCENTRATION IS ATTAINED AT APPROXIMATELY 1.5 TO 3.67 HOURS AFTER INGESTION. THE HALF-LIFE IS MEASURED TO BE ABOUT 4 HOURS 12 .
CLEARANCE
NOT AVAILABLE
TOXICITY
LD50: >5 G/KG IN RATS, ORALLY ,15 . SOME COMMON ADVERSE EFFECTS INCLUDE HOT FLASHES, FLUSHING OF THE FACE, AND HEADACHE. ELEVATION IN SERUM TOTAL CHOLESTEROL, ALT (SGPT), AST (SGOT) AND BUN MAY ALSO OCCUR. FREQUENT URINATION, PEDAL EDEMA, INCREASED TRIGLYCERIDES HAVE BEEN FOUND TO OCCUR IN LESS THAN 0.1% OF PATIENTS.
THE SERUM CONCENTRATION OF (R)-WARFARIN CAN BE INCREASED WHEN IT IS COMBINED WITH EFONIDIPINE.
(S)-WARFARIN THE SERUM CONCENTRATION OF (S)-WARFARIN CAN BE INCREASED WHEN IT IS COMBINED WITH EFONIDIPINE.
1-BENZYLIMIDAZOLE 1-BENZYLIMIDAZOLE MAY DECREASE THE ANTIHYPERTENSIVE ACTIVITIES OF EFONIDIPINE.
2,4-THIAZOLIDINEDIONE THE RISK OR SEVERITY OF HYPOGLYCEMIA CAN BE INCREASED WHEN EFONIDIPINE IS COMBINED WITH 2,4-THIAZOLIDINEDIONE.
2,5-DIMETHOXY-4-ETHYLAMPHETAMINE 2,5-DIMETHOXY-4-ETHYLAMPHETAMINE MAY DECREASE THE ANTIHYPERTENSIVE ACTIVITIES OF EFONIDIPINE.
2,5-DIMETHOXY-4-ETHYLTHIOAMPHETAMINE 2,5-DIMETHOXY-4-ETHYLTHIOAMPHETAMINE MAY DECREASE THE ANTIHYPERTENSIVE ACTIVITIES OF EFONIDIPINE.
4-BROMO-2,5-DIMETHOXYAMPHETAMINE 4-BROMO-2,5-DIMETHOXYAMPHETAMINE MAY DECREASE THE ANTIHYPERTENSIVE ACTIVITIES OF EFONIDIPINE.
4-HYDROXYCOUMARIN THE METABOLISM OF 4-HYDROXYCOUMARIN CAN BE DECREASED WHEN COMBINED WITH EFONIDIPINE.
4-METHOXYAMPHETAMINE 4-METHOXYAMPHETAMINE MAY DECREASE THE ANTIHYPERTENSIVE ACTIVITIES OF EFONIDIPINE.
5-METHOXY-N,N-DIMETHYLTRYPTAMINE 5-METHOXY-N,N-DIMETHYLTRYPTAMINE MAY DECREASE THE ANTIHYPERTENSIVE ACTIVITIES OF EFONIDIPINE.
7,8-DICHLORO-1,2,3,4-TETRAHYDROISOQUINOLINE 7,8-DICHLORO-1,2,3,4-TETRAHYDROISOQUINOLINE MAY INCREASE THE HYPOTENSIVE ACTIVITIES OF EFONIDIPINE.
9-AMINOCAMPTOTHECIN THE METABOLISM OF 9-AMINOCAMPTOTHECIN CAN BE DECREASED WHEN COMBINED WITH EFONIDIPINE.
ABACAVIR EFONIDIPINE MAY INCREASE THE EXCRETION RATE OF ABACAVIR WHICH COULD RESULT IN A LOWER SERUM LEVEL AND POTENTIALLY A REDUCTION IN EFFICACY.
ABAFUNGIN THE THERAPEUTIC EFFICACY OF ABAFUNGIN CAN BE INCREASED WHEN USED IN COMBINATION WITH EFONIDIPINE.
ABEDITEROL ABEDITEROL MAY DECREASE THE ANTIHYPERTENSIVE ACTIVITIES OF EFONIDIPINE.
ABEXINOSTAT THE RISK OR SEVERITY OF QTC PROLONGATION CAN BE INCREASED WHEN EFONIDIPINE IS COMBINED WITH ABEXINOSTAT.
ABIRATERONE THE METABOLISM OF ABIRATERONE CAN BE DECREASED WHEN COMBINED WITH EFONIDIPINE.
ACALABRUTINIB THE METABOLISM OF ACALABRUTINIB CAN BE DECREASED WHEN COMBINED WITH EFONIDIPINE.
ACARBOSE EFONIDIPINE MAY INCREASE THE EXCRETION RATE OF ACARBOSE WHICH COULD RESULT IN A LOWER SERUM LEVEL AND POTENTIALLY A REDUCTION IN EFFICACY.
ACEBUTOLOL THE RISK OR SEVERITY OF BRADYCARDIA CAN BE INCREASED WHEN EFONIDIPINE IS COMBINED WITH ACEBUTOLOL.
ACECLOFENAC THE THERAPEUTIC EFFICACY OF EFONIDIPINE CAN BE DECREASED WHEN USED IN COMBINATION WITH ACECLOFENAC.
ACEMETACIN THE THERAPEUTIC EFFICACY OF EFONIDIPINE CAN BE DECREASED WHEN USED IN COMBINATION WITH ACEMETACIN.
ACENOCOUMAROL THE SERUM CONCENTRATION OF ACENOCOUMAROL CAN BE INCREASED WHEN IT IS COMBINED WITH EFONIDIPINE.
ACEPROMAZINE THE RISK OR SEVERITY OF HYPOTENSION CAN BE INCREASED WHEN ACEPROMAZINE IS COMBINED WITH EFONIDIPINE.
ACEPROMETAZINE THE RISK OR SEVERITY OF QTC PROLONGATION CAN BE INCREASED WHEN EFONIDIPINE IS COMBINED WITH ACEPROMETAZINE.
ACETAMINOPHEN EFONIDIPINE MAY INCREASE THE EXCRETION RATE OF ACETAMINOPHEN WHICH COULD RESULT IN A LOWER SERUM LEVEL AND POTENTIALLY A REDUCTION IN EFFICACY.
ACETOHEXAMIDE THE RISK OR SEVERITY OF HYPOGLYCEMIA CAN BE INCREASED WHEN EFONIDIPINE IS COMBINED WITH ACETOHEXAMIDE.
ACETYLDIGITOXIN EFONIDIPINE MAY INCREASE THE ARRHYTHMOGENIC ACTIVITIES OF ACETYLDIGITOXIN.
ACETYLDIGOXIN EFONIDIPINE MAY INCREASE THE ARRHYTHMOGENIC ACTIVITIES OF ACETYLDIGOXIN.
ACETYLSALICYLIC ACID ACETYLSALICYLIC ACID MAY DECREASE THE EXCRETION RATE OF EFONIDIPINE WHICH COULD RESULT IN A HIGHER SERUM LEVEL.
ACLIDINIUM EFONIDIPINE MAY INCREASE THE EXCRETION RATE OF ACLIDINIUM WHICH COULD RESULT IN A LOWER SERUM LEVEL AND POTENTIALLY A REDUCTION IN EFFICACY.
ACRIVASTINE EFONIDIPINE MAY INCREASE THE EXCRETION RATE OF ACRIVASTINE WHICH COULD RESULT IN A LOWER SERUM LEVEL AND POTENTIALLY A REDUCTION IN EFFICACY.
ACYCLOVIR EFONIDIPINE MAY INCREASE THE EXCRETION RATE OF ACYCLOVIR WHICH COULD RESULT IN A LOWER SERUM LEVEL AND POTENTIALLY A REDUCTION IN EFFICACY.
ADENOSINE EFONIDIPINE MAY INCREASE THE ARRHYTHMOGENIC ACTIVITIES OF ADENOSINE.
ADRAFINIL ADRAFINIL MAY DECREASE THE ANTIHYPERTENSIVE ACTIVITIES OF EFONIDIPINE.
AGMATINE AGMATINE MAY INCREASE THE ARRHYTHMOGENIC ACTIVITIES OF EFONIDIPINE.
AICA RIBONUCLEOTIDE THE RISK OR SEVERITY OF HYPOGLYCEMIA CAN BE INCREASED WHEN EFONIDIPINE IS COMBINED WITH AICA RIBONUCLEOTIDE.
AJMALINE AJMALINE MAY INCREASE THE ARRHYTHMOGENIC ACTIVITIES OF EFONIDIPINE.
ALBACONAZOLE THE THERAPEUTIC EFFICACY OF ALBACONAZOLE CAN BE INCREASED WHEN USED IN COMBINATION WITH EFONIDIPINE.
ALBENDAZOLE THE METABOLISM OF ALBENDAZOLE CAN BE DECREASED WHEN COMBINED WITH EFONIDIPINE.
ALBIGLUTIDE THE RISK OR SEVERITY OF HYPOGLYCEMIA CAN BE INCREASED WHEN EFONIDIPINE IS COMBINED WITH ALBIGLUTIDE.
ALBUTREPENONACOG ALFA EFONIDIPINE MAY INCREASE THE EXCRETION RATE OF ALBUTREPENONACOG ALFA WHICH COULD RESULT IN A LOWER SERUM LEVEL AND POTENTIALLY A REDUCTION IN EFFICACY.
ALCLOFENAC THE THERAPEUTIC EFFICACY OF EFONIDIPINE CAN BE DECREASED WHEN USED IN COMBINATION WITH ALCLOFENAC.
ALCURONIUM EFONIDIPINE MAY INCREASE THE NEUROMUSCULAR BLOCKING ACTIVITIES OF ALCURONIUM.
ALDESLEUKIN ALDESLEUKIN MAY INCREASE THE EXCRETION RATE OF EFONIDIPINE WHICH COULD RESULT IN A LOWER SERUM LEVEL AND POTENTIALLY A REDUCTION IN EFFICACY.
ALECTINIB THE METABOLISM OF ALECTINIB CAN BE DECREASED WHEN COMBINED WITH EFONIDIPINE.
ALFENTANIL THE THERAPEUTIC EFFICACY OF EFONIDIPINE CAN BE DECREASED WHEN USED IN COMBINATION WITH ALFENTANIL.
ALFUZOSIN THE METABOLISM OF ALFUZOSIN CAN BE DECREASED WHEN COMBINED WITH EFONIDIPINE.
ALIMEMAZINE THE RISK OR SEVERITY OF QTC PROLONGATION CAN BE INCREASED WHEN ALIMEMAZINE IS COMBINED WITH EFONIDIPINE.
ALISKIREN THE RISK OR SEVERITY OF HYPERKALEMIA CAN BE INCREASED WHEN ALISKIREN IS COMBINED WITH EFONIDIPINE.